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Nav1.7-A1632G Mutation from a Family with Inherited Erythromelalgia: Enhanced Firing of Dorsal Root Ganglia Neurons Evoked by Thermal Stimuli.

ABSTRACT: UNLABELLED:Voltage-gated sodium channel Nav1.7 is a central player in human pain. Mutations in Nav1.7 produce several pain syndromes, including inherited erythromelalgia (IEM), a disorder in which gain-of-function mutations render dorsal root ganglia (DRG) neurons hyperexcitable. Although patients with IEM suffer from episodes of intense burning pain triggered by warmth, the effects of increased temperature on DRG neurons expressing mutant Nav1.7 channels have not been well documented. Here, using structural modeling, voltage-clamp, current-clamp, and multielectrode array recordings, we have studied a newly identified Nav1.7 mutation, Ala1632Gly, from a multigeneration family with IEM. Structural modeling suggests that Ala1632 is a molecular hinge and that the Ala1632Gly mutation may affect channel gating. Voltage-clamp recordings revealed that the Nav1.7-A1632G mutation hyperpolarizes activation and depolarizes fast-inactivation, both gain-of-function attributes at the channel level. Whole-cell current-clamp recordings demonstrated increased spontaneous firing, lower current threshold, and enhanced evoked firing in rat DRG neurons expressing Nav1.7-A1632G mutant channels. Multielectrode array recordings further revealed that intact rat DRG neurons expressing Nav1.7-A1632G mutant channels are more active than those expressing Nav1.7 WT channels. We also showed that physiologically relevant thermal stimuli markedly increase the mean firing frequencies and the number of active rat DRG neurons expressing Nav1.7-A1632G mutant channels, whereas the same thermal stimuli only increase these parameters slightly in rat DRG neurons expressing Nav1.7 WT channels. The response of DRG neurons expressing Nav1.7-A1632G mutant channels upon increase in temperature suggests a cellular basis for warmth-triggered pain in IEM. SIGNIFICANCE STATEMENT:Inherited erythromelalgia (IEM), a severe pain syndrome characterized by episodes of intense burning pain triggered by warmth, is caused by mutations in sodium channel Nav1.7, which are preferentially expressed in sensory and sympathetic neurons. More than 20 gain-of-function Nav1.7 mutations have been identified from IEM patients, but the question of how warmth triggers episodes of pain in IEM has not been well addressed. Combining multielectrode array, voltage-clamp, and current-clamp recordings, we assessed a newly identified IEM mutation (Nav1.7-A1632G) from a multigeneration family. Our data demonstrate gain-of-function attributes at the channel level and differential effects of physiologically relevant thermal stimuli on the excitability of DRG neurons expressing mutant and WT Nav1.7 channels, suggesting a cellular mechanism for warmth-triggered pain episodes in IEM patients.

SUBMITTER: Yang Y

PROVIDER: S-EPMC6705539 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Nav1.7-A1632G Mutation from a Family with Inherited Erythromelalgia: Enhanced Firing of Dorsal Root Ganglia Neurons Evoked by Thermal Stimuli.

Yang Yang Y Yang Yang Y Huang Jianying J Mis Malgorzata A MA Estacion Mark M Macala Lawrence L Shah Palak P Schulman Betsy R BR Horton Daniel B DB Dib-Hajj Sulayman D SD Waxman Stephen G SG

The Journal of neuroscience : the official journal of the Society for Neuroscience 20160701 28

<h4>Unlabelled</h4>Voltage-gated sodium channel Nav1.7 is a central player in human pain. Mutations in Nav1.7 produce several pain syndromes, including inherited erythromelalgia (IEM), a disorder in which gain-of-function mutations render dorsal root ganglia (DRG) neurons hyperexcitable. Although patients with IEM suffer from episodes of intense burning pain triggered by warmth, the effects of increased temperature on DRG neurons expressing mutant Nav1.7 channels have not been well documented. H ...[more]

PMID: 27413160

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Project description:Inherited erythromelalgia (IEM) causes debilitating episodic neuropathic pain characterized by burning in the extremities. Inherited "paroxysmal extreme pain disorder" (PEPD) differs in its clinical picture and affects proximal body areas like the rectal, ocular, or jaw regions. Both pain syndromes have been linked to mutations in the voltage-gated sodium channel Nav1.7. Electrophysiological characterization shows that IEM-causing mutations generally enhance activation, whereas mutations leading to PEPD alter fast inactivation. Previously, an A1632E mutation of a patient with overlapping symptoms of IEM and PEPD was reported (Estacion, M., Dib-Hajj, S. D., Benke, P. J., Te Morsche, R. H., Eastman, E. M., Macala, L. J., Drenth, J. P., and Waxman, S. G. (2008) NaV1.7 Gain-of-function mutations as a continuum. A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms of both disorders. J. Neurosci. 28, 11079-11088), displaying a shift of both activation and fast inactivation. Here, we characterize a new mutation of Nav1.7, A1632T, found in a patient suffering from IEM. Although transfection of A1632T in sensory neurons resulted in hyperexcitability and spontaneous firing of dorsal root ganglia (DRG) neurons, whole-cell patch clamp of transfected HEK cells revealed that Nav1.7 activation was unaltered by the A1632T mutation but that steady-state fast inactivation was shifted to more depolarized potentials. This is a characteristic normally attributed to PEPD-causing mutations. In contrast to the IEM/PEPD crossover mutation A1632E, A1632T failed to slow current decay (i.e. open-state inactivation) and did not increase resurgent currents, which have been suggested to contribute to high-frequency firing in physiological and pathological conditions. Reduced fast inactivation without increased resurgent currents induces symptoms of IEM, not PEPD, in the new Nav1.7 mutation, A1632T. Therefore, persistent and resurgent currents are likely to determine whether a mutation in Nav1.7 leads to IEM or PEPD.

Project description:The Nav1.7 channel critically contributes to the excitability of sensory neurons, and gain-of-function mutations of this channel have been shown to cause inherited erythromelalgia (IEM) with neuropathic pain. In this study, we report a case of a severe phenotype of IEM caused by p.V1316A mutation in the Nav1.7 channel. Mechanistically, we first demonstrate that the Nav?4 peptide acts as a gating modifier rather than an open channel blocker competing with the inactivating peptide to give rise to resurgent currents in the Nav1.7 channel. Moreover, there are two distinct open and two corresponding fast inactivated states in the genesis of resurgent Na+ currents. One is responsible for the resurgent route and practically existent only in the presence of Nav?4 peptide, whereas the other is responsible for the "silent" route of recovery from inactivation. In this regard, the p.V1316A mutation makes hyperpolarization shift in the activation curve, and depolarization shift in the inactivation curve, vividly uncoupling inactivation from activation. In terms of molecular gating operation, the most important changes caused by the p.V1316A mutation are both acceleration of the transition from the inactivated states to the activated states and deceleration of the reverse transition, resulting in much larger sustained as well as resurgent Na+ currents. In summary, the genesis of the resurgent currents in the Nav1.7 channel is ascribable to the transient existence of a distinct and novel open state promoted by the Nav?4 peptide. In addition, S4-5 linker in domain III where V1316 is located seems to play a critical role in activation-inactivation coupling, chiefly via direct modulation of the transitional kinetics between the open and the inactivated states. The sustained and resurgent Na+ currents may therefore be correlatively enhanced by specific mutations involving this linker and relevant regions, and thus marked hyperexcitability in corresponding neural tissues as well as IEM symptomatology.

Dataset Information

Nav1.7-A1632G Mutation from a Family with Inherited Erythromelalgia: Enhanced Firing of Dorsal Root Ganglia Neurons Evoked by Thermal Stimuli.

Publications

Nav1.7-A1632G Mutation from a Family with Inherited Erythromelalgia: Enhanced Firing of Dorsal Root Ganglia Neurons Evoked by Thermal Stimuli.

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